For metastatic prostate cancer (PCa), androgen deprivation therapy results in regression of the metastatic disease and a dramatic decrease in the serum of the androgen dependent prostate-specific antigen (PSA) protein. Eventually, all patients will fail this therapy because the cancer will become "androgen refractory" and progresses to "Castrate Resistant Prostate Cancer" (CRPC). A central theme now emerging is that CRPC is still dependent upon androgen receptor (AR) signaling. We provide compelling evidence that activation of NF- ?B is sufficient to maintain castrate resistant growth of the prostate via regulating androgen receptor action. To provide proof for this mechanism, we have shown that constitutive activation of NF- ?B in the mouse prostate is sufficient to prevent regression of the prostate following castration by maintaining extremely high levels of nuclear AR and continued epithelial cell proliferation. Androgen ablation (castration) of PB-Hi-myc mice results in decreased AR levels and regression of the prostate cancer. However, androgen ablated NF- ?B/PB-Hi-myc mice still maintain high levels of AR and the tumor continues to proliferate at castrated levels of androgens. The loss of Pten in the mouse prostate results in the adenocarcinoma. Further, the loss of Pten results in increased AR levels and continued prostatic proliferation in castrated mice. Our HYPOTHESIS is that the activation of the NF- ?B pathway and the down-regulation of Pten co-operate resulting in castration resistant prostate cancer. We will test our hypothesis by studying the molecular mechanisms of NF- ?B and Pten interaction in following Specific Aims: 1. To determine the contribution of Pten and NF- ?B signaling to AR action in vitro. 2. To investigate the function of Pten and NF- ?B signaling on androgen regulation of growth. 3. To test if blocking NF- ?B activity is sufficient to reverse prostatic proliferation. Results from our animal studies will have a high-impact on explaining failure to androgen-ablation therapy and in defining new routes of therapeutic intervention in relapsed patients. PUBLIC HEALTH RELEVANCE: For metastatic prostate cancer, androgen deprivation therapy results in regression of the metastatic disease. Eventually, all prostate cancer patients fail androgen ablation therapy. Results from our animal studies will have a high-impact of explaining failure to androgen-ablation therapy and in defining new routes of therapeutic intervention.